Little Paul, Francis Nick A, Stuart Beth, O’Reilly Gilly, Thompson Natalie, Becque Taeko, Hay Alastair D, Wang Kay, Sharland Michael, Harnden Anthony, Yao Guiqing, Raftery James, Zhu Shihua, Little Joseph, Hookham Charlotte, Rowley Kate, Euden Joanne, Harman Kim, Coenen Samuel, Read Robert C, Woods Catherine, Butler Christopher C, Faust Saul N, Leydon Geraldine, Wan Mandy, Hood Kerenza, Whitehurst Jane, Richards-Hall Samantha, Smith Peter, Thomas Michael, Moore Michael, and Verheij Theo
Background Antimicrobial resistance is a global health threat. Antibiotics are commonly prescribed for children with uncomplicated lower respiratory tract infections, but there is little randomised evidence to support the effectiveness of antibiotics in treating these infections, either overall or relating to key clinical subgroups in which antibiotic prescribing is common (chest signs; fever; physician rating of unwell; sputum/rattly chest; shortness of breath). Objectives To estimate the clinical effectiveness and cost-effectiveness of amoxicillin for uncomplicated lower respiratory tract infections in children both overall and in clinical subgroups. Design Placebo-controlled trial with qualitative, observational and cost-effectiveness studies. Setting UK general practices. Participants Children aged 1–12 years with acute uncomplicated lower respiratory tract infections. Outcomes The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). Secondary outcomes were symptom severity on days 2–4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; complications; side effects; and resource use. Methods Children were randomised to receive 50 mg/kg/day of oral amoxicillin in divided doses for 7 days, or placebo using pre-prepared packs, using computer-generated random numbers by an independent statistician. Children who were not randomised could participate in a parallel observational study. Semistructured telephone interviews explored the views of 16 parents and 14 clinicians, and the data were analysed using thematic analysis. Throat swabs were analysed using multiplex polymerase chain reaction. Results A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The primary analysis imputed missing data for 115 children. The duration of moderately bad symptoms was similar in the antibiotic and placebo groups overall (median of 5 and 6 days, respectively; hazard ratio 1.13, 95% confidence interval 0.90 to 1.42), with similar results for subgroups, and when including antibiotic prescription data from the 326 children in the observational study. Reconsultations for new or worsening symptoms (29.7% and 38.2%, respectively; risk ratio 0.80, 95% confidence interval 0.58 to 1.05), illness progression requiring hospital assessment or admission (2.4% vs. 2.0%) and side effects (38% vs. 34%) were similar in the two groups. Complete-case (n = 317) and per-protocol (n = 185) analyses were similar, and the presence of bacteria did not mediate antibiotic effectiveness. NHS costs per child were slightly higher (antibiotics, £29; placebo, £26), with no difference in non-NHS costs (antibiotics, £33; placebo, £33). A model predicting complications (with seven variables: baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often, and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.83) and calibration. Parents found it difficult to interpret symptoms and signs, used the sounds of the child’s cough to judge the severity of illness, and commonly consulted to receive a clinical examination and reassurance. Parents acknowledged that antibiotics should be used only when ‘necessary’, and clinicians noted a reduction in parents’ expectations for antibiotics. Limitations The study was underpowered to detect small benefits in key subgroups. Conclusion Amoxicillin for uncomplicated lower respiratory tract infections in children is unlikely to be clinically effective or to reduce health or societal costs. Parents need better access to information, as well as clear communication about the self-management of their child’s illness and safety-netting. Future work The data can be incorporated in the Cochrane review and individual patient data meta-analysis. Trial registration This trial is registered as ISRCTN79914298. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information. Plain language summary Background Children are commonly prescribed antibiotics for chest infections, but such infections are becoming resistant to antibiotics, and it is not clear if antibiotics work in treating them. Methods A total of 432 children who saw their general practitioner with a chest infection were given either an antibiotic (amoxicillin) or a placebo (no antibiotic) for 7 days. Symptom diaries documented the infection’s duration and its side effects. Children not in the placebo study were able to participate in another study that documented the same outcomes (an ‘observational study’). We interviewed parents, doctors and nurses about their observations and concerns. Our patient and public involvement and engagement work with parents indicated that a 3-day symptom reduction was required to justify giving antibiotics. Results After seeing the doctor, parents whose children received antibiotics rated infective symptoms as moderately bad or worse for 5 days, and parents whose children received the placebo rated these for 6 days. Side effects and complications were similar in the two groups. Findings were similar when including the results of the observational study, and for children in whose chest the doctor could hear wheeze or rattles; who had fever; who were rated by the doctor as more unwell, who were short of breath, or who had had bacteria detected in the throat. The costs to the NHS per child were similar (antibiotics, £29; placebo, £26), and the wider costs to society were the same (antibiotics, £33; placebo, £33). Parents found it difficult to interpret their child’s symptoms, and commonly used the sound of the cough to judge severity. Parents commonly consulted to receive an examination and reassurance, and accepted that antibiotics should be used only when ‘necessary’. Clinicians noted a reduction in parents’ expectations for antibiotics. Conclusion Amoxicillin for chest infections in children is unlikely to be effective. General practitioners should support parents to self-manage at home and give clear communication about when and how to seek medical help if they continue to be concerned. Scientific summary Background Antimicrobial resistance (AMR) is a global public health threat. Antibiotics are very commonly prescribed for children presenting with uncomplicated lower respiratory tract infection, but there is little randomised evidence of the effectiveness of antibiotics for treating these, either overall or among key clinical subgroups. Objective The objective was to undertake a trial of antibiotics for children presenting with lower respiratory tract infection in primary care, with a parallel observational study. Aims The aims were to: 1.estimate the effectiveness of amoxicillin overall and in key clinical subgroups of children presenting with uncomplicated (non-pneumonic) lower respiratory tract infection in primary care 2.estimate the cost-effectiveness of antibiotics overall in children presenting with uncomplicated (non-pneumonic) lower respiratory tract infection in primary care 3.explore the estimates of effectiveness according to key pathophysiological subgroups (the presence of bacterial pathogens) 4.explore which variables predict poor prognosis and develop a prediction model for poor prognosis 5.explore the views of parents and clinicians regarding management of children and participation in the trial. Design This was a placebo-controlled trial with qualitative research and health economic analysis, and a parallel observational cohort. Setting UK general practices. Participants Participants were children aged between 6 months and 12 years presenting to primary care with an acute lower respiratory tract infection, defined as one in which an acute cough is the predominant symptom and judged by the general practitioner (GP) to be infective in origin, lasting < 21 days, and with other symptoms or signs localising to the lower respiratory tract (shortness of breath, sputum, pain), and in whom pneumonia was not suspected clinically. Outcomes The primary outcome was the duration in days of symptoms rated moderately bad or worse (measured using a validated diary). The secondary outcomes were symptom severity on days 2–4 (0 = no problem to 6 = as bad as it could be); symptom duration until very little/no problem; reconsultations for new or worsening symptoms; progression of illness sufficient to require hospital assessment; side effects; and resource use. Ethics The protocol was approved by the South West – Central Bristol Research Ethics Committee (reference 15/SW/0300). Methods Children were randomised to receive 50 mg/kg/day oral amoxicillin in divided doses for 7 days, or placebo, using pre-prepared packs randomised by an independent statistician using computer-generated random numbers. Children whom clinicians were unwilling to randomise or parents who were unwilling for their child to be randomised were invited to participate in an observational study in which the same data as in the trial were collected. The revised target sample size (agreed with the Trial Steering Committee, the Data Monitoring and Ethics Committee and the funder) to detect an important clinical difference of 3 days in symptoms duration was 298 participants for 80% power and 398 participants for 90% power. Semistructured interviews were used to explore the views of management and the decisions to participate in the trial. Parents were purposefully sampled by whether they took part in the trial or the observational study, and by practice. Clinicians who recruited participants into the study were also invited to take part in a telephone interview. The interviews were analysed using thematic analysis. Throat swabs were analysed for the presence of bacteria and viruses by multiplex polymerase chain reaction. Statistical analysis Cox regression was used for the primary outcome and for total symptom duration, adjusting for age, baseline symptom severity, prior duration of illness and comorbidity. Linear regression was used for symptom severity, and logistic regression was used for reconsultation, progression of illness and side effects, adjusting for the same baseline covariates as in the primary analysis. Analysis was by intention to treat, as randomised regardless of non-adherence or protocol deviations. Multiple imputation was used as the primary analysis, comprising all variables from the analysis model and any predictors of missingness, and using 100 imputations. Prespecified subgroup analyses were carried out on chest signs, sputum/rattly chest, history of fever, physician rating of unwell, shortness of breath, oxygen saturation below 95%, and STARWAVe clinical prediction rule for hospitalisation. For the observational data set, stratification by propensity scores was used to control for confounding by indication, and the data were merged with the trial data set to facilitate more powerful analyses. A logistic regression model was built to predict the progression of illness, and discrimination was assessed using estimates of area under the receiver operator curve that were bootstrapped for internal validation. Health economic analysis Both cost-effectiveness (in GBP per unit of primary outcome) and cost per quality-adjusted life-year (QALY) were estimated. The base case took an NHS perspective, but some non-NHS costs were also included (remedies and time off work). Resource use data were collected by a notes review in primary care supplemented by the diary. Unit costs of primary care consultation, community services, outpatient visits and accident and emergency attendances were costed based on the Personal Social Services Research Unit. National reference costs were used to cost hospital stay based on corresponding diagnostic categories. Medications were priced based on the British National Formulary. All costs were based on 2019 prices. QALYs were based on the EQ-5D-Y (EuroQol-5 Dimensions Youth), collected weekly, and on the recommended national tariff. Trial results A total of 432 children were randomised (antibiotics, n = 221; placebo, n = 211). The duration of moderately bad symptoms was similar in the two groups [median 5 vs. 6 days, respectively; hazard ratio (HR) 1.13, 95% confidence interval (CI) 0.90 to 1.42]. Return with new or worsening symptoms (29.7% vs. 38.2%; risk ratio 0.80, 95% CI 0.58 to 1.05), progression of illness requiring hospital assessment (2.4% vs 2.0%) and side effects (38% vs. 34%) were also similar in the two groups. A small difference in mean symptom severity on days 2–4 (1.8 vs. 2.1 points; difference 0.28 points, 95% CI 0.04 to 0.51) is unlikely to be clinically meaningful. No differences were seen for the primary outcome in the five prespecified clinical subgroups in which antibiotic prescribing is common: chest signs subgroup (antibiotics 6 days vs. placebo 6 days; HR 0.97, 95% CI 0.65 to 1.43), sputum/rattly chest (5 vs. 7 days; 1.16, 95% CI 0.83 to 1.64), fever (5 vs. 6 days; 1.23, 95% CI 0.88 to 1.73), physician rating of unwell (5 vs. 6 days; 1.25, 95% CI 0.85 to 1.83) and shortness of breath (5 vs. 6 days; 1.13, 95% CI 0.72 to 1.77). There was also no evidence that the presence of bacteria in the throat swab mediated antibiotic effectiveness. Estimates from complete cases (n = 317) were very similar, as were estimates from a per-protocol analysis for children taking 11 or more of the of 15 doses in the first 5 days. NHS costs per child were slightly higher with antibiotics (antibiotic, £29; placebo, £26) and non-NHS costs were the same (antibiotics, £33; placebo, £33), but QALY data were too incomplete for robust imputation. The incremental cost per QALY (incremental cost-effectiveness ratio) was £30,851 (95% CI –£73,639 to £109,429) based on estimates from the means of complete cases and £6417 (95% CI –£12,240 to £20,535) based on the estimates using imputed data. Observational study A total of 326 children were recruited to the observational study. The estimate of benefit of antibiotics for the primary outcome was similar to that in the trial (HR 1.16, 95% CI 0.95 to 1.41). A prognostic model to predict the progression of illness consisting of seven variables (baseline severity, difference in respiratory rate from normal for age, duration of prior illness, oxygen saturation, sputum/rattly chest, passing urine less often and diarrhoea) had good discrimination (bootstrapped area under the receiver operator curve 0.85) and calibration, and a three-item model (respiratory rate, oxygen saturation, sputum/rattly chest) also performed well (area under the receiver operator curve 0.81). Qualitative results Thirty semistructured telephone interviews were conducted with 16 parents and 14 clinicians. Parents found it difficult to interpret the symptoms and signs, and commonly used the sounds of the cough to judge severity, which highlights the need to provide better information to support parents. Many parents said that the main reason for consulting was to receive a clinical examination and reassurance regarding illness severity. Parents acknowledged that antibiotics should be used only when ‘necessary’, and many of the clinicians also noted a shift in parents’ expectations about antibiotics and that they were satisfied with a clinical assessment, reassurance and advice. Decisions to take part in the trial were influenced by the perceived risks associated with taking a placebo compared with immediate antibiotics, and with taking antibiotics unnecessarily. Clear communication about the self-management of their child’s illness and ‘safety-netting’ (information on the natural course of the illness and advice about when it might be necessary to reconsult) were identified as important when implementing ‘no antibiotic’ prescribing strategies to reassure parents and to support prescribing decisions. Limitations The study was underpowered to detect small benefits in the key clinical subgroups. The trial included children who were more unwell than those in recent large generalisable cohorts, which suggests that, if anything, the benefit of antibiotics has been overestimated. Given the very large numbers of missing data, the imputed estimates in the economic analysis must be viewed with caution. If the costs of AMR were included, then these estimates of cost-effectiveness would worsen. Conclusions Implications for clinical care Amoxicillin for uncomplicated chest infections in children makes little difference to symptom burden or to health or societal costs. Better access to information is needed to support parents’ decision-making, as is clear clinician communication about the self-management of their child’s illness and safety-netting. A prognostic score using variables that can be collected very easily during consultations can be used to identify children who are at low risk of illness progression. Implications for future research •The data can be incorporated in a Cochrane review and an individual patient data meta-analysis. •Further work on the incremental QALY gain from antibiotics is needed, assessing a range of models and their implications when imputing missing QALY data, and better evidence is needed about how to incorporate AMR resource implications in modelling. •The prognostic score should be externally validated and could be developed as an app with automated outputs, and thereafter used as a tool to reduce antibiotic prescribing for antimicrobial stewardship interventions. Trial registration This trial is registered as ISRCTN79914298. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 9. See the NIHR Journals Library website for further project information.